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V. Raymond, S. Dubois, J. Anctil, A. Duchesne, M. Faucher, M. Rodrigue, Québec Glaucoma Network, J. Morissette; Large Scale Screening of Optineurin (OPTN) Glaucoma-causing Mutations in the French-Canadian Population of Québec . Invest. Ophthalmol. Vis. Sci. 2003;44(13):1130.
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Purpose: Optineurin (OPTN ) was recently characterized as the second open-angle glaucoma gene (OAG) mapped to GLC1E at 10p14 (Science (2002) 295: 1077). OPTN mutations were reported as more common in normal tension glaucoma (NTG) patients than in persons affected by primary open-angle glaucoma (POAG), a form of OAG often associated with elevated intra-ocular pressures. To assess prevalence of OPTN mutations in Québec, we screened its 13 coding exons for variations in 354 unrelated glaucoma patients. Methods: 292 POAG, 62 NTG and 56 investigated normal persons (matched for age) were recruited in the Province of Québec, Canada. Virtually all were French-Canadians. The 13 exons encoding OPTN protein (exons 4-16) and their intron-exon junctions were screened by direct genomic sequencing using intronic primers. Results: A minimum of 269 POAG and 52 NTG subjects were sequenced for each of the 13 exons. Exon 5 was sequenced on both strands in 283 POAG and 52 NTG persons. Six sequence alterations were detected. Two of these encoded amino acid (AA) changes while the other 4 were SNPs that did not alter the wild-type AA. One of the AA changes was the previously identified M98K risk-associated variation encoded in exon 5. This alteration was detected in 16/283 POAG (5.6%), 4/52 NTG (7.7%) and 3/56 investigated normal (5.4%) subjects. An exact Fisher test led to a value p=0.7365 for these 3 groups, suggesting no statistical difference between them. Although none of the 3 previously described mutations (ie: E50K, c.691_692insAG premature stop, R545Q) was detected, we observed a novel K59N variation in 1/283 POAG and 1/56 normal individuals. Two SNPs were detected in exon 4: the 412G>A (T34T) and the 433G>A (L41L) observed, respectively, in about 35% and 8/335 of all glaucoma patients. Two SNPs were also detected in exon 6: the 712C>A (A134A) and 799A>G (E163E). Excluding SNP T34T, out of the 32 patients who carried the 5 other OPTN alterations, only 1 harbored a TIGR/myocilin mutation (Ala445Val). Conclusions: As proportions of OPTNM98K subjects were not significantly different in the POAG, NTG and normal groups, our data suggest that this risk-associated variation should be further evaluated by following-up asymptomatic carriers and investigating the families of the glaucoma carriers. More French-Canadian patients and new populations should be investigated to test if the novel K59N alteration is a polymorphism or a disease-causing mutation.
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